Cellular Sources Of Neuregulin 1 (NRG1) Regulating Neural Activity And Behavior

项目摘要 精神分裂症(Sz)影响全球1%的人口，给患者带来昂贵而痛苦的负担， 他们的家庭和社会。目前还没有有效的治疗方法来恢复SZ患者的健康。这个 神经营养因子神经调节蛋白1(NRG1)是一个很有前途的治疗靶点，因为该基因与 Sz在不同的人群中，NRG1水平在Sz发生了变化。NRG1刺激酪氨酸ErbB家族 激酶受体，包括与Sz相关的ErbB4。ErbB4受体介导的NRG1信号转导 在小白蛋白(PV)阳性的中间神经元促进对执行功能重要的神经过程 在Sz中受到损害。在改善SZ治疗方面取得进展的一个关键障碍是缺乏对 无论是产生导致GABA释放的NRG1的细胞还是刺激伽马振荡的细胞， 也提供参与抑制LTP或癫痫活动的NRG1。我们的目标是提高治疗水平 通过获得设计能够平息癫痫的药物所需的信息和理解来了解Sz 而不会抑制涉及学习和记忆的神经机制。我们的中心假设是 不同细胞来源的NRG1对突触传递、网络活动有不同的选择性影响 和行为，这些独特的细胞功能是NRG1可能通过的机制 抑制癫痫发作，促进网络活动，对更高的大脑功能至关重要。我们的目标是 1)确定神经元和星形细胞NRG1在GABA传递中的细胞类型特异性作用 振荡、LTP、癫痫发生和Sz相关的小鼠行为和2)提供细胞 NRG1的来源涉及局部回路中兴奋-抑制平衡的调节机制，以及 促进信息从海马体到皮质的转移。我们的预期结果包括1)知识 在参与突触和网络活动的不同状态的NRG1的细胞起源中，2)改善 对ErbB4激活NRG1的神经元和星形细胞机制的理解，以及3)新的 洞察星形胶质细胞和神经元NRG1在需要认知的行为中所扮演的特定角色 Sz中的功能经常受损。我们的发现的影响将为治疗提供更有力的理论基础 在病理情况下以NRG1为目标，以及改进的知识库，这是 设计能够在不抑制参与学习和学习的神经机制的情况下平息癫痫的药物 记忆。目标1将检验NRG1起源于主神经元、中间神经元和星形胶质细胞的假设 不同地调节兴奋性和抑制性突触传递。目标2将检验NRG1的假设 来源于这三种不同类型的细胞对Sz相关行为有不同的调节作用。

Project Summary Schizophrenia (Sz) affects 1% of the population worldwide and places a costly and painful burden on patients, their families and society. Currently there are no treatments available to effectively rehabilitate Sz patients. The neurotrophic factor Neuregulin 1 (NRG1) is a promising therapeutic target because the gene is associated with Sz in various populations, and NRG1 levels are altered in Sz. NRG1 stimulates the ErbB family of tyrosine kinase receptors, including ErbB4, which is associated with Sz. NRG1 signaling via ErbB4 receptors expressed in parvalbumin (PV)-positive interneurons promotes neural processes important for executive functions which are impaired in Sz. A critical barrier to progress in improving treatment of Sz is a lack of understanding of whether the cells, which produce the NRG1 resulting in release of GABA or stimulation of gamma oscillations, also supply the NRG1 involved in suppression of LTP or seizure activity. Our goal is to improve the treatment of Sz by obtaining the information and understanding needed for designing drugs capable of quelling seizures without inhibiting neural mechanisms involved in learning and memory. Our central hypothesis is that different cellular sources of NRG1 differentially and selectively impact synaptic transmission, network activity and behavior, and that these unique cellular functions are potential mechanisms by which NRG1 could suppress seizures as well as promote network activity important for higher brain functions. Our objectives are to 1) determine the cell-type specific roles of neuronal and astrocytic NRG1 in GABA transmission, gamma oscillations, LTP, epileptogenesis, and Sz-relevant mouse behaviors and 2) provide clarification of the cellular sources of NRG1 involved in mechanisms regulating excitatory-inhibitory balance within local circuits, and facilitating transfer of information from hippocampus to cortex. Our expected outcomes include 1) knowledge of the cellular origins of NRG1 engaged during different states of synaptic and network activity, 2) improved understanding of the neuronal and astrocytic mechanisms underpinning NRG1 activation of ErbB4, and 3) new insights into the specific roles played by astrocytic and neuronal NRG1 in behaviors requiring cognitive functions often impaired in Sz. The impact of our findings will provide a stronger rationale for therapeutically targeting NRG1 during pathological conditions, as well as an improved knowledge base, which is needed for designing drugs capable of quelling seizures without inhibiting neural mechanisms involved in learning and memory. Aim 1 will test the hypothesis that NRG1 derived from principal neurons, interneurons and astrocytes differentially regulates excitatory and inhibitory synaptic transmission. Aim 2 will test the hypothesis that NRG1 derived from these three different cell types differentially regulate Sz-relevant behaviors.